In our previous paper we have reported the synthesis and biological activity of a cyclic analog, Tyr-c(D-Lys-
Phe-Phe-Asp)-NH2, based on endomorphin-2 (EM-2) structure. This analog displayed high affinity for the µ-opioid receptor,
was much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular
(i.c.v.) injection. Even more importantly, the cyclic analog elicited weak analgesia also after peripheral
administration, giving evidence that it was able to cross, at least to some extent, the blood-brain barrier (BBB). Here
we describe further modifications of this analog aimed at enhancing brain delivery by increasing lipophilicity. Two new
cyclic pentapeptides, Tyr-c(D-Lys-D-1-Nal-Phe-Asp)-NH2 and Tyr-c(D-Lys-D-2-Nal-Phe-Asp)-NH2 (where 1-Nal=1-
naphthyl-3-alanine, 2-Nal=2-naphthyl-3-alanine) were synthesized and evaluated in biological assays. Both analogs
showed high µ-opioid receptor affinity and agonist activity and were stable in the rat brain homogenates. Unfortunately,
the increase of lipophilicity was achieved at the expense of water solubility. The analog with D-2-Nal residue showed
strong analgesic effect when given i.c.v. but could not be tested after intravenous (i.v.) administration where higher
concentrations of the compound are required. However, this analog showed inhibitory effect on gastrointestinal (GI) motility
in vivo, providing an interesting approach to the development of peripherally restricted agents that could be useful
for studying gastrointestinal disorders in animal models.
Keywords: Binding studies, µ-, δ- opioid receptor, hot-plate test, solid phase peptide synthesis, blood-brain barrier, lipophilicity.
Rights & PermissionsPrintExport